Editor's Summary

Follicle Architects in the Colonic Mucosa

Experimental Salmonella infections in the colon of mice are associated with a heterogeneous infiltrate of inflammatory myeloid cells including a predominance of cells expressing the CX3CR1 chemokine receptor. Koscsó et al. used a fluorescent reporter mouse strain to separate the inflammatory myeloid infiltrate into subsets of cells with low, intermediate, and high levels of CX3CR1 expression. RNA sequencing analysis provided clues to the functional roles of each subset. The CX3CR1hi macrophages were enriched within tertiary lymphoid structures that developed at mucosal sites of Salmonella invasion and contributed to induction of localized IgA antibody responses to Salmonella through expression of CXCL13, TGF-β1, and IL-10. These findings enhance our understanding of the functional diversification of the macrophage subsets associated with colonic inflammation.

Abstract

Intestinal mononuclear phagocytes (MPs) are composed of heterogeneous dendritic cell (DC) and macrophage subsets necessary for the initiation of immune response and control of inflammation. Although MPs in the normal intestine have been extensively studied, the heterogeneity and function of inflammatory MPs remain poorly defined. We performed phenotypical, transcriptional, and functional analyses of inflammatory MPs in infectious Salmonella colitis and identified CX3CR1+ MPs as the most prevalent inflammatory cell type. CX3CR1+ MPs were further divided into three distinct populations, namely, Nos2+CX3CR1lo, Ccr7+CX3CR1int (lymph migratory), and Cxcl13+CX3CR1hi (mucosa resident), all of which were transcriptionally aligned with macrophages and derived from monocytes. In follow-up experiments in vivo, intestinal CX3CR1+ macrophages were superior to conventional DC1 (cDC1) and cDC2 in inducing Salmonella-specific mucosal IgA. We next examined spatial organization of the immune response induced by CX3CR1+ macrophage subsets and identified mucosa-resident Cxcl13+CX3CR1hi macrophages as the antigen-presenting cells responsible for recruitment and activation of CD4+ T and B cells to the sites of Salmonella invasion, followed by tertiary lymphoid structure formation and the local pathogen-specific IgA response. Using mice we developed with a floxed Ccr7 allele, we showed that this local IgA response developed independently of migration of the Ccr7+CX3CR1int population to the mesenteric lymph nodes and contributed to the total mucosal IgA response to infection. The differential activity of intestinal macrophage subsets in promoting mucosal IgA responses should be considered in the development of vaccines to prevent Salmonella infection and in the design of anti-inflammatory therapies aimed at modulating macrophage function in inflammatory bowel disease.